CN103045667A - Preparation method of S-(+)-2-aminobutanamide hydrochloride - Google Patents
Preparation method of S-(+)-2-aminobutanamide hydrochloride Download PDFInfo
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- CN103045667A CN103045667A CN2012104669557A CN201210466955A CN103045667A CN 103045667 A CN103045667 A CN 103045667A CN 2012104669557 A CN2012104669557 A CN 2012104669557A CN 201210466955 A CN201210466955 A CN 201210466955A CN 103045667 A CN103045667 A CN 103045667A
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Abstract
The invention provides a production method of S-(+)-2-aminobutanamide hydrochloride which is a key intermediate necessary for synthesizing anti-epileptic chiral drug, namely levetiracetam. The method comprises the following steps of: using L-threonine as an initial raw material, preparing L-2-aminobutyric acid by using a biotransformation method, and then performing esterification and ammonolysis reaction to obtain a target compound. According to the method provided by the invention, biotransformation and chemical synthesis are combined, and the good optical selectivity of the biotransformation is utilized for generating the L-2-aminobutyric acid, the reaction condition is mild and simple, the raw material cost is low, an organic solvent is not necessary, the process is environment-friendly, the purity of an isomer is high, and both the conversion rate and the yield are high; and therefore, the S-(+)-2-aminobutanamide hydrochloride is suitable for industrial production.
Description
Technical field
The present invention relates to the synthetic required key intermediate of a kind of anti-epileptic chiral drug Levetiracetam
SThe preparation method of-(+)-2-amino-butanamide hydrochloride belongs to the technical field of chipal compounds.
Background technology
Levetiracetam (Levetiracetam), it is the pyrrolidone kind new medicine with brand-new anti-epileptic mechanism by the research and development of Belgian UCB. S.A. (BE) Bruxelles Belgium, being mainly used in treating limitation and secondary generalized epilepsy, is unique wide spectrum antiepileptic drug with prophylactic effect of reporting at present.The Etiracetam of having gone on the market has
R,
STwo kinds of optics enantiomers.The right Etiracetam of its dextrorotatory form only has slight or unconspicuous drug action for suppressing epileptic seizures, and the levo form Levetiracetam is a kind of safely and efficiently antiepileptic drug, can effectively control epileptic seizures, compare with right Etiracetam and have the characteristics such as therapeutic index height, security is good, side effect is slight.
Present Levetiracetam synthesis technique, mainly be with
S-(+)-2-amino-butanamide hydrochloride reacts to prepare Levetiracetam as key intermediate and chiral source by itself and 4-chlorobutanoylchloride, and wherein, the optical purity of levoisomer is the synthetic key of Levetiracetam in the control reaction process.Existing
S-(+)-2-amino-butanamide hydrochloride mainly is to utilize Split Method to obtain.
Chinese patent CN1583721A discloses a kind of optically pure by splitting DL (±)-2-amino-butanamide hydrochloride acquisition
SThe method of-(+)-2-amino-butanamide hydrochloride.But in actually operating because split process alkali, such as the existence of sodium hydroxide, make quite a few inorganic salts in the system, such as sodium tartrate etc. and product Precipitation simultaneously, cause the product separation difficulty, finally make the product purity that obtains not high.In addition, the method is not recycled another isomer that produces in the reaction process, makes this route cost higher, and yield is lower.
The disclosed method of Chinese patent CN101130504B is to obtain 2-amino-butyric acid through amination take the 2-bromo-butyric acid as raw material in ammoniacal liquor, then obtain DL free alkali (±)-2-amino-butanamide crude product through esterification ammonia solution, adopt again the method for Resolution, be combined into chemical resolving agent and salt out, reach the purpose of separation and purification, further obtain optically active
S-(+)-2-amino-butanamide hydrochloride.But (±)-2-amino-butanamide crude product contains more unknown impuritie in actual production, and follow-up fractionation and purification procedures are made a big impact, and environment hidden danger is large, and easily causes unstable product quality, makes and be subject to certain limitation in the production.
Summary of the invention
The objective of the invention is to provide in order to solve the problems of the technologies described above that a kind of purity is high, yield is high, it is few to pollute
SThe preparation method of-(+)-2-amino-butanamide hydrochloride, the method is efficient, low-cost, is easy to industrialization production.
Technical solution of the present invention is:
SA kind of preparation method of-(+)-2-amino-butanamide hydrochloride, take L-threonine as starting raw material, make C4H9NO2 through the conversion of intestinal bacteria whole-cell biological, resulting C4H9NO2 makes optically active through esterification and ammonolysis reaction again
S-(+)-2-amino-butanamide hydrochloride.
Further, bioconversion reaction of the present invention is to carry out in water solution system, the full cell of intestinal bacteria in the described bioconversion reaction comprises one or both combinations of the full cell of A type intestinal bacteria or the full cell of Type B intestinal bacteria, is preferably two kinds of combinations of the full cell of A type intestinal bacteria and the full cell of Type B intestinal bacteria.The full cell of the type of A described in the present invention intestinal bacteria is the gene engineering colibacillus that contains L-threonine deaminase gene plasmid, and the full cell of described Type B intestinal bacteria is the gene engineering colibacillus that contains L-Leu dehydrogenase gene plasmid and formate dehydrogenase gene plasmid.
Further, in the described bioconversion reaction, with aqueous solution volumeter, the add-on of L-threonine is 20-120g/l, and the add-on of the full cell of A type intestinal bacteria is 2-8g/l, and the add-on of the full cell of Type B intestinal bacteria is 10-40g/l.Described bioconversion reaction carries out under 25～38 ℃ of conditions of temperature, reacts to obtain C4H9NO2 in 6～28 hours.Also be added with ammonium formiate in the described bioconversion reaction, the add-on of ammonium formiate is 1～1.3 times of molar equivalent of L-threonine add-on.
Further, esterification of the present invention be the C4H9NO2 that obtains take described bioconversion reaction as raw material, under the thionyl chloride catalytic condition and the lower alcohol reaction generate
S-(+)-2-amino-butyric acid ester hydrochloride.The mol ratio of described thionyl chloride and C4H9NO2 is 1.1～1.4:1, and the mol ratio of described lower alcohol and C4H9NO2 is 10～15:1, and described lower alcohol is methyl alcohol or ethanol, is preferably methyl alcohol.In the described esterification reaction process, described thionyl chloride is dropped in the reaction system of the C4H9NO2 of 0～8 ℃ of temperature and lower alcohol, drip duration 2～5 hours, under 8-20 ℃ of condition, react after thionyl chloride drips and finishes and obtained in 4～18 hours
S-(+)-2-amino-butyric acid ester hydrochloride.
Again further, ammonolysis reaction of the present invention is to obtain with described esterification
S-(+)-2-amino-butyric acid ester hydrochloride generates under the effect of saturated ammoniacal liquor
S-(+)-2-amino-butanamide hydrochloride, described ammoniacal liquor with
SThe mass ratio that feeds intake of-(+)-2-amino-butyric acid ester hydrochloride is 5～8:1:.Described ammonolysis reaction carries out under 0～10 ℃ of condition of temperature, reacts to obtain optically active in 10～22 hours
S-(+)-2-amino-butanamide hydrochloride.
The method that the present invention adopts bio-transformation and chemosynthesis to combine prepares the synthetic required key intermediate of anti-epileptic chiral drug Levetiracetam
S-(+)-2-amino-butanamide hydrochloride, because the enforcement of above technical scheme than existing production technique, has following advantage:
⑴ employing optical purity enantiomer C4H9NO2 is the chiral source synthesis of optically active
S-(+)-2-amino-butanamide hydrochloride avoided splitting the loss chiral raw material, and product yield is high, purity is high, and reaction process is not used organic solvent, the technique environmental protection, and simple to operate.
⑵ adopt resting cell to replace the enzyme process reaction, and process is simpler, avoids simultaneously using the coenzyme such as expensive NAD, and raw materials cost is lower, and aftertreatment is more simple, and these characteristics make the cost of C4H9NO2, are conducive to large-scale industrial production.
⑶ go on foot respectively that starting material are cheap and easy to get, and unit operation is simple, and equipment requirements is low, pollutes fewly, and product purity is high, is suitable for large-scale industrial production.
Embodiment
Below in conjunction with specific examples technical solution of the present invention is described further, for embodiment method of the present invention is made the generality illustration, help to understand better the present invention, but can't limit the scope of the invention.
According to the present invention, the described full cell derived reference of the A type intestinal bacteria method that contains the gene engineering colibacillus of L-threonine deaminase gene plasmid makes up (AbreScia P, et, al. Threonine deaminaSe:AutogenouS regulator of the ilv geneS in EScherichia coli K-12. Molecular and General GeneticS MGG, 1979,171,261-275), the full cell of A type intestinal bacteria adds the PLP(5-pyridoxal phosphate when enlarged culturing).The described full cell derived of Type B intestinal bacteria that contains the gene engineering colibacillus of L-Leu desaturase and formate dehydrogenase gene plasmid makes up (Galkin in the reference method, A, et, al. SyntheSiS of optically active amino acidS from alpha-keto acidS with EScherichia coli cellS expreSSing heterologouS geneS. Applied and environmental microbiology, 1997,63 (12), 4651).The commercially available acquisitions of raw material such as L-threonine, ammonium formiate, thionyl chloride, methyl alcohol, ethanol and ammoniacal liquor.
" embodiment 1 "
1.1 bioconversion reaction
In the flask that the 500ml band stirs, add L-threonine 10g, ammonium formiate 6.7g, the full cell of 0.8gA type intestinal bacteria, the full cell of 4.0gB type intestinal bacteria is dissolved in the 200ml water, keeps 32 ℃ of bath temperatures, mixing speed 500rpm.The HPLC tracking monitor transforms situation, and 24h transforms greater than 99%, stopped reaction.Centrifugal removal somatic cells dewaters the supernatant liquor vacuum decompression, is concentrated into 20ml, filters behind the crystallisation by cooling, uses 100ml methanol wash post-drying again, gets the white solid 6.7g of 2-amino-butyric acid, and yield is 77.4%, purity〉99%, the ee value〉99%.
1H-NMR（400MHz，D
2O）δ0.814(3H，CH
3)，1.728(2H,CH
2)，3.545(H,CH)。
⒈ 2 esterifications
In the flask that the 100ml band stirs, add the 6.7g C4H9NO2, methyl alcohol 30ml stirs 200-250rpm, 4 ℃ of temperature, slowly evenly drip thionyl chloride 12ml, about control time for adding 3h, dropwise 20 ℃ of control temperature of reaction, behind the 15h, transformation efficiency〉99%, concentrating under reduced pressure is removed methyl alcohol, obtains white solid after the oven dry
S-(+)-2-amino-butyric acid methyl ester hydrochloride 10.0g.
⒈ 3 ammonolysis reactions
In the flask that 100ml band stirs, prepare in advance and be pre-chilled to 4 ℃ saturated ammoniacal liquor 70ml, add the white solid that the 10.0g esterification obtains, mixing speed 200-250rpm keeps temperature of reaction 0-4 ℃, behind the 18hr, transformation efficiency〉99%, the concentrating under reduced pressure desolventizing obtains after the vacuum-drying
SThe white solid 7.5g of-(+)-2-amino-butanamide hydrochloride, yield 83.3%, purity 99.2%.
1H-NMR（400MHz，D
2O）δ1.383（t，3H),2.623(m，2H),5.372(t，H)；
13C-NMR(400MHz,D
2O)δ10.962（CH
3），26.848（CH
2），56.702（CH），174.851（C0）。
" embodiment 2 "
2.1 bioconversion reaction
In the flask that the 500ml band stirs, add L-threonine 20g, ammonium formiate 15.2g, the full cell of 2.0gA type intestinal bacteria, the full cell of 10.0gB type intestinal bacteria is dissolved in the 200ml water, keeps 32 ℃ of bath temperatures, mixing speed 500rpm.The HPLC tracking monitor transforms situation, and 24h transforms greater than 99%, stopped reaction.Centrifugal removal somatic cells dewaters the supernatant liquor vacuum decompression, is concentrated into 25ml, filters behind the crystallisation by cooling, uses 100ml methanol wash post-drying again, gets white solid C4H9NO2 14.1g, and yield is 81.4%, purity〉99%, the ee value〉99%.
2.2 esterification
In the flask that the 250ml band stirs, add the 14.1g C4H9NO2, methyl alcohol 60ml stirs 200-250rpm, 4 ℃ of temperature, slowly evenly drip thionyl chloride 25ml, about control time for adding 3h, dropwise 20 ℃ of control temperature of reaction, behind the 15h, transformation efficiency〉99%, concentrating under reduced pressure is removed methyl alcohol, obtains white solid after the oven dry
S-(+)-2-amino-butyric acid methyl ester hydrochloride 21.0g.
2.3 ammonolysis reaction
In the flask that the 250ml band stirs, prepare in advance and be pre-chilled to 4 ℃ saturated ammoniacal liquor 150ml, add the white solid that the 21.0g esterification obtains, mixing speed 200-250rpm keeps temperature of reaction 0-4 ℃, behind the 18hr, transformation efficiency〉99%, the concentrating under reduced pressure desolventizing obtains white solid S-(+)-2-amino-butanamide hydrochloride 16.3g after the vacuum-drying, yield 86.0%, purity 99.3%.
" embodiment 3 "
3.1 bioconversion reaction
In the flask that the 2000ml band stirs, add L-threonine 120g, ammonium formiate 75.2g, the full cell of 6.0gA type intestinal bacteria, the full cell of 32.0g Type B intestinal bacteria is dissolved in the 1000ml water, keeps 32 ℃ of bath temperatures, mixing speed 500rpm.The HPLC tracking monitor transforms situation, and 24h transforms greater than 99%, stopped reaction.Centrifugal removal somatic cells dewaters the supernatant liquor vacuum decompression, is concentrated into 25ml, filters behind the crystallisation by cooling, uses 100ml methanol wash post-drying again, gets white solid C4H9NO2 85.3g, and yield is 82.2%, purity〉99%, the ee value〉99%.
⒊ 2 esterifications
In the flask that the 1000ml band stirs, add the 85.3gL-2-aminobutyric acid, methyl alcohol 380ml stirs 200-250rpm, 4 ℃ of temperature, slowly evenly drip thionyl chloride 82ml, about control time for adding 3h, dropwise 20 ℃ of control temperature of reaction, behind the 15h, transformation efficiency〉99%, concentrating under reduced pressure is removed methyl alcohol, obtains white solid after the oven dry
S-(+)-2-amino-butyric acid methyl ester hydrochloride 127.2g.
3.3 ammonolysis reaction
In the flask that the 1000ml band stirs, prepare in advance and be pre-chilled to 4 ℃ saturated ammoniacal liquor 450ml, add the white solid that the 127.2g esterification obtains, mixing speed 200-250rpm, keep temperature of reaction 0-4 ℃, behind the 16hr, transformation efficiency〉99%, the concentrating under reduced pressure desolventizing obtains white solid after the vacuum-drying
S-(+)-2-amino-butanamide hydrochloride 94.3g, yield 82.6%, purity 99.3%.
Claims (10)
1.
SThe preparation method of-(+)-2-amino-butanamide hydrochloride, it is characterized in that: take L-threonine as starting raw material, make C4H9NO2 through the conversion of intestinal bacteria whole-cell biological, resulting C4H9NO2 makes optically active through esterification and ammonolysis reaction again
S-(+)-2-amino-butanamide hydrochloride.
2. according to claim 1
SThe preparation method of-(+)-2-amino-butanamide hydrochloride, it is characterized in that: described bioconversion reaction is to carry out in water solution system, and the full cell of the intestinal bacteria in the described bioconversion reaction comprises one or both combinations of the full cell of A type intestinal bacteria or the full cell of Type B intestinal bacteria; The full cell of described A type intestinal bacteria is the gene engineering colibacillus that contains L-threonine deaminase gene plasmid; The full cell of described Type B intestinal bacteria is the gene engineering colibacillus that contains L-Leu dehydrogenase gene plasmid and formate dehydrogenase gene plasmid.
3. according to claim 2
SThe preparation method of-(+)-2-amino-butanamide hydrochloride, it is characterized in that: in the described bioconversion reaction, with aqueous solution volumeter, the add-on of L-threonine is 20-120g/l, the add-on of the full cell of A type intestinal bacteria is 2-8g/l, and the add-on of the full cell of Type B intestinal bacteria is 10-40g/l.
4. according to claim 1
SThe preparation method of-(+)-2-amino-butanamide hydrochloride is characterized in that: described bioconversion reaction carries out under 25～38 ℃ of conditions of temperature, 6～28 hours reaction times.
5. according to claim 1
SThe preparation method of-(+)-2-amino-butanamide hydrochloride is characterized in that: also be added with ammonium formiate in the described bioconversion reaction, the add-on of ammonium formiate is 1～1.3 times of molar equivalent of L-threonine add-on.
6. according to claim 1
SThe preparation method of-(+)-2-amino-butanamide hydrochloride is characterized in that: described esterification be the C4H9NO2 that obtains take described bioconversion reaction as raw material, under the thionyl chloride catalytic condition and the lower alcohol reaction generate
S-(+)-2-amino-butyric acid ester hydrochloride; The mol ratio of described thionyl chloride and C4H9NO2 is 1.1～1.4:1, and the mol ratio of described lower alcohol and C4H9NO2 is 10～15:1.
7. according to claim 6
SThe preparation method of-(+)-2-amino-butanamide hydrochloride is characterized in that: described lower alcohol is methyl alcohol or ethanol.
8. according to claim 1
SThe preparation method of-(+)-2-amino-butanamide hydrochloride, it is characterized in that: in the described esterification reaction process, described thionyl chloride is dropped in the reaction system of the C4H9NO2 of 0～8 ℃ of temperature and lower alcohol, drip duration 2～5 hours, dropping was reacted 4～18 hours under 8-20 ℃ of condition after finishing.
9. according to claim 1
SThe preparation method of-(+)-2-amino-butanamide hydrochloride is characterized in that: described ammonolysis reaction is to obtain with described esterification
S-(+)-2-amino-butyric acid ester hydrochloride generates under the effect of saturated ammoniacal liquor
S-(+)-2-amino-butanamide hydrochloride, described ammoniacal liquor with
SThe mass ratio that feeds intake of-(+)-2-amino-butyric acid ester hydrochloride is 5～8:1.
10. according to claim 1
SThe preparation method of-(+)-2-amino-butanamide hydrochloride is characterized in that: described ammonolysis reaction carries out under 0～10 ℃ of condition of temperature, 10～22 hours reaction times.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104478663A (en) * | 2014-12-20 | 2015-04-01 | 郁庆明 | Preparation method of high-quality S-2-chlorobutanol |
| CN104774881A (en) * | 2015-04-10 | 2015-07-15 | 湖南福来格生物技术有限公司 | Method for producing L-2-aminobutyric acid by virtue of biological catalysis |
| CN109134341A (en) * | 2018-09-19 | 2019-01-04 | 黑龙江珍宝岛药业股份有限公司 | A kind of preparation method of Levetiracetam |
| CN111440083A (en) * | 2020-04-30 | 2020-07-24 | 贵州联科中贝制药科技有限公司 | Preparation method of (S) - (+) -2-aminobutanamide hydrochloride |
| CN112195203A (en) * | 2020-11-10 | 2021-01-08 | 江苏八巨药业有限公司 | Method for synthesizing (S) -2-aminobutanamide by enzyme method |
| CN114409586A (en) * | 2021-12-23 | 2022-04-29 | 山东诚汇双达药业有限公司 | Preparation method of levetiracetam |
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104478663A (en) * | 2014-12-20 | 2015-04-01 | 郁庆明 | Preparation method of high-quality S-2-chlorobutanol |
| CN104478663B (en) * | 2014-12-20 | 2017-06-20 | 郁庆明 | The preparation method of the methaforms of high-quality S 2 |
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| CN112195203A (en) * | 2020-11-10 | 2021-01-08 | 江苏八巨药业有限公司 | Method for synthesizing (S) -2-aminobutanamide by enzyme method |
| CN112195203B (en) * | 2020-11-10 | 2022-07-26 | 江苏八巨药业有限公司 | Method for synthesizing (S) -2-aminobutanamide by enzyme method |
| CN114409586A (en) * | 2021-12-23 | 2022-04-29 | 山东诚汇双达药业有限公司 | Preparation method of levetiracetam |
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Application publication date: 20130417 |